The NMDA receptor antagonist MK-801 prevents long-lasting non-associative morphine tolerance in the rat

Brain Res. 1992 Mar 20;575(2):304-8. doi: 10.1016/0006-8993(92)90094-p.


Several studies have demonstrated that the N-methyl-D-aspartate (NMDA) antagonist MK-801 attenuates the development of morphine tolerance and withdrawal. These studies employed repeated morphine injections to induce tolerance, a procedure in which learning has been suggested to play a significant role in tolerance development. MK-801 has been reported to block some types of learning, and it is unclear, therefore, whether the effect of MK-801 on tolerance development is due to its antagonism of associative (learning) or non-associative factors. Moreover, previous studies have tested the effects of MK-801 on morphine tolerance only up to 48 h after its induction; yet morphine tolerance can persist for many months, and it is not known whether MK-801 can block long-lasting tolerance. In the present study, therefore, we adopted a model of morphine tolerance in which the involvement of learning is minimized by using a single injection of morphine in a sustained-release preparation, and we tested tolerance for up to 56 days. In the first experiment, simultaneously administering MK-801 (0.2 mg/kg, s.c.) and morphine (60 mg/kg, s.c.), each in a sustained-release preparation, abolished tolerance that lasted at least 12 days. Analgesia was measured in the hot-plate test following a test dose of morphine (15 mg/kg, i.p.). In the second experiment, delivering MK-801 and morphine as before, the duration of morphine-induced catalepsy and analgesia was prolonged. Nevertheless, 24 h later one symptom of naloxone-precipitated withdrawal was significantly attenuated in these same animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesia
  • Animals
  • Catalepsy / chemically induced
  • Dizocilpine Maleate / pharmacology*
  • Drug Tolerance
  • Male
  • Morphine / metabolism*
  • Morphine / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors


  • Receptors, N-Methyl-D-Aspartate
  • Dizocilpine Maleate
  • Morphine